1. Field of the Invention
The present invention relates generally to the field of medical and biological adhesives and encompasses more specifically the closing of microsurgical and large wounds in delicate tissues as well repair of tissue defects by medical and biological adhesives.
2. Description of the Related Art
The conventional methods of choice to close incisions in soft tissue following surgery, injury and the like have been sutures and staples in spite of the limitations which are inherent in these mechanical approaches. For example, tissue incompatibility with sutures or staples may cause fistulas granulomas and neuromas which are painful and difficult to treat. Sutures and staples may also tend to cut through weak parenchymatous or poorly vascularized tissue. Sutures also leave behind a tract which can allow for leakage of fluids and organisms. The needle for any suture is larger than the thread attached to it. This causes a problem as the needle tract is larger than can be filled by the thread.
In addition, limits are imposed by the required manual dexterity and eyesight of the surgeon and the excessive amount of time that is required for the use of sutures or staples in microsurgeries. Finally, even when properly applied, the joints in the gaps between the staples or sutures may be inherently weak or may structurally weaken over time and will leak.
Several investigators have worked on laser closure of wounds (White et al., 1986; White, J. V., 1989; Oz and Bass et al., 1989; White et al., 1987). Early contributions concentrated on welding tissues using lasers of different wavelengths applied directly to wound edges. Investigating the microstructural basis of the tissue fusion thus produced, Schober and coworkers proposed that there occurred a "homogenizing change in collagen with interdigitation of altered individual fibrils" (Schober et al., 1986). These investigators, as well as others, proposed that the concentrated heating of the collagen fibrils above a threshold level allowed for their cross-linking (Goosey et al., 1980; Chacon et al., 1988; Tanzer, M. L., 1973). Unfortunately, the heat necessary to allow this reaction to occur causes collateral thermal damage. Even a slight distortion, in ocular tissue for example, may have functional consequences. Also, in the event of laser weld failure, the edges of the tissues may be damaged by the original treatment and cannot be re-exposed to laser energy (Oz, 1990).
Further work attempted to enhance heat-activated cross-linking by placing a dye in the wound. It was reported that matching the absorbance of the dye with the laser wavelength, allowed an adhesive effect to be achieved with less laser power output and collateral thermal injury (Chuck et al., 1989; Foote, C. S., 1976; Oz M. C. and Chuck et al, 1989). Coupling the dye with a protein to create a tissue "solder" was also investigated. The protein of choice has been fibrinogen, and in particular autologous fibrinogen in order to avoid problems of the transfer of viral diseases through the use of blood components from pool donors. In previous applications, fibrinogen has been obtained as a fraction of whole blood. It is not pure fibrinogen, but also contains other blood elements, such as clotting factors. Application of such a protein-dye mixture in various animal models proved to be an improvement to dye alone (Oz et al., 1990; Moazami et al., 1990). Unfortunately, human application was forestalled owing to the need to isolate the needed protein (fibrinogen) from the patient prior to the procedure to avoid the risks of infection from donor plasma. Work with albumin found it to be an unsatisfactory substitute as it did not yield welds of comparable strength.
Comparisons of protein-dye versus sutured closures have found the protein-dye group to produce less of an inflammatory response, result in greater collagen production, greater mean peak stress at rupture and better cosmesis (Wider et al., 1991). Ophthalmologic application of such a tissue solder has included the sealing of conjunctival blebs (Weisz, et al., 1989), sclerostomy (Odrich et al., 1989), closure of retinectomies (Wolf et al., 1989), and thermokeratoplasty (Wapner et al., 1990) using similar mixtures.
Although several tissue adhesives have been formulated, few have seen widespread use clinically. "Laser-activated" tissue glues have been used in skin closures as well as vascular and bowel anastomoses (Chuck et al., 1989; Moazami et al., 1990; Wider et al., 1991; Auteri et al., 1992). The most successful product thus far is a mixture of cryoprecipitated fibrinogen and a dye that absorbs laser energy and releases it in the form of heat at the wound interface (Moazami, et al., 1990; Oz et al., 1990).
Because of the urgent need for a satisfactory method of closing wounds and surgical incisions in ocular tissue, the inventors tried systematically to find the best combination of protein and laser induced heat-generating dye for use in the eye. The results of this study led the inventors to conclude that all wounds closed in this manner are unsatisfactory. Adequate bond strengths in human cadaver sclera were only achieved at the cost of obvious protein denaturation and tissue distortion around the wound site. The process was arduous due to sclera's tendency to shrink when exposed to heat and the seal thus obtained diminished markedly in strength when immersed in water. This is especially important in vascular anastomoses or for any anastomoses of a fluid containing structure such as the eye, aorta, ureter and GI tract, in which the fluid contents may leak out. This is in addition to the problems mentioned above when fluids and bacteria may leak into a wound. In an environment such as the eye, overcoming this drawback was crucial to the success of the method of wound closure.
Although much work has been done in this area, there is still no method of closing wounds in tissues that does not have serious limitations. What is needed in the art is a method of producing a fast, water tight seal of a wound without the mechanical problems and manual dexterity associated with sutures and staples, and without the distortion and collateral tissue damage caused by heat-generating methods of wound closure.